( PDF ) Rev Osteoporos Metab Miner. 2011 3 (1): 5-6

Sosa Henríquez M1, Vicente Barrero M2, Bocanegra Pérez S2
1 Universidad de Las Palmas de Gran Canaria- Grupo de investigación en osteoporosis y metabolismo mineral
2 Hospital Universitario Insular – Servicio de Cirugía Maxilofacial – Las Palmas de Gran Canaria


Maxillary osteonecrosis (MON) is a disease which has appeared recently as a serious complication in patients suffering from neoplasms or other chronic diseases. MON has been associated with the use of powerful diphosphonates, for which reason many authors have named the disease secondary osteonecrosis of the mandible due to biphosphonates1-5.
This is a relatively new disease, which means that there is not yet unanimity on many of its aspects. For a start, there is no clear and universally accepted definition of MON. A panel of experts from the American Society of Bone and Mineral Research (ASBMR)2 recently recommended using the definition “an area of exposed bone which persists for more than 8 weeks in the absence of earlier irradiation and/or metastasis in the mandible”. The American Academy of Mouth and Maxillofacial Surgeons published a similar definition: a patient may have MON if they comply with 3 requirements: 1) current or previous use of biphosphonates; 2) the presence exposed or necrotic bone for a minimum of 8 weeks; and 3) an absence of maxillary radiotherapy. At this point should insist that the correct name for the disease is maxillary necrosis and not necrosis of the mandible, given that there is frequently also affectation of the upper maxilla6.
It used to be thought generally that MON was directly related to the use of biphosphonates, above all with those that are most powerful and administered intravenously, such as zoledronic acid or pamidronate. Thus, prestigious authors such as Reid have described MON as “a complication in the use of high doses of biphosphonates, which is characterised by the appearance of exposed bone in the oral cavity”7.
The pathogeny of MON is unknown up until now, for which reason various theories relating to this have been developed1,6,8,9. Given that it has not been possible to identify one single cause, many authors have implicated various etiopathogenic factors, some of which may act in conjunction. In one way or another, the biphosphonates have always been present in these etiopathogenic theories. For example, one of these is based on the bone toxicity of biphosphonates, according to which the drug would accumulate in the bone in sufficient quantities to be directly toxic to the oral epithelium1. This would result in inadequate healing of lesions in the soft tissues, such as those observed in invasive dental procedures or by traumas produced by poorly-fitted prostheses, which could result in a secondary infection in the underlying bone10. However, against this theory, we have the fact that only the maxillas are affected, and not other bones where biphosphonates act equally. Another slightly different theory is that the biphosphonates accumulate in the alveolar bone, both in the upper maxilla and in the mandible, producing toxicity in the region of the soft tissues instead of in the bone7.
However, against the theory that biphosphonates are the cause of MON we have, firstly, the fact that up to 25% of cases of MON have been described in patients who had not received this drug6,8,10-14. Secondly, many other risk factors have been described for this disease, such as diabetes mellitus, taking corticoids, immunosuppressive treatment and rheumatoid arthritis, to name but a few6,11,15,16. These etiopathogenic factors are not mutually exclusive. In fact it is possible that MON could be a disease with a multifactorial etiopathogeny. On the other hand, it should also be taken into account that in up to 70% of cases there has been a dental intervention, such as teeth extraction, implants, etc.3-6,8,10,14,16.
Finally, MON has been described in patients receiving denosumab, a monoclonal antibody against the protein RANKL, in 2 studies carried out in patients affected by cancer and who were randomly chosen to receive this drug, or zoledronic acid. In the first report, the prevalence of MON was 1.1% in those patients receiving denosumab and 1.3% in those who received zoledronic acid17. In another study, the prevalence of MON was 2% in those receiving denosumab and 1.4% in those who received zoledronic acid18.
In conclusion, the new descriptions of MON in patients receiving denosumab ought to drive us towards re-examining the etiopathology of MON. Perhaps this disease is caused by an excessive repression of bone remodelling in patients with neoplasms, in whom the dose of these antiresorptive drugs used greatly exceeds that recommended for osteoporosis.
1. Bartl R MG. Bisphosphonateassociated osteonecrosis of the jaw: a pathophysiologic approach. Bone 2008;42(Suppl 1):76.
2. Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, et al. Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007;22:1479-91.
3. Marx RE, Sawatari Y, Fortin M, Broumand V. Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 2005;63:1567-75.
4. Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 2004;62:527-34.
5. V Broumand RM. Risk factors, recognition, prevention, treatment of bisphosphonate-induced osteonecrosis of the jaws. J Oral Maxillofac Surg 2006;64:96.
6. Sosa Henríquez M, Gómez de Tejada Romero MJ, Bagán Sebastián JV, Díaz Curiel M, Díez Pérez A, E JG, et al. Osteonecrosis de los maxilares. Documento de consenso. Rev Osteoporos Metab Miner 2009;1:41-52.
7. Reid IR BM, Grey AB. Is bisphosphonate-associated osteonecrosis of the jaw caused by soft tissue toxicity? Bone 2007;41:318-20.
8. Reid I. Pathogenesis of osteonecrosis of the Jaw. IBMS Bonekey 2008;2:69-77.
9. Bagán J, Blade J, Cozar J, Constela M, García Sanz R, Gómez Veiga F, et al. Recomendaciones para la prevención, diagnóstico y tratamiento de osteonecrosis de los maxilares (ONM) en pacientes con cáncer tratados con bifosfonatos. Med Oral Patol Oral Cir Bucal 2007;12:279-83.
10. Reid IR. Osteonecrosis of the jaw: who gets it, and why? Bone 2009;44:4-10.
11. Sambrook PN, Ebeling P. Osteonecrosis of the jaw. Curr Rheumatol Rep 2008;10:97-101.
12. Marx RE, Cillo JE, Jr, Ulloa JJ. Oral bisphosphonate-induced osteonecrosis: risk factors, prediction of risk using serum CTX testing, prevention, and treatment. J Oral Maxillofac Surg 2007;65:2397-410.
13. Cartsos VM ZS, Zavras AI. Bisphosphonate use and the risk of adverse jaw outcomes: a medical claims study of 714,217 people. J Am Dent Assoc 2008;139:23-30.
14. Woo S-B, Hellstein JW, JR K. Systematic review: Bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 2006;144:753-61.
15. Kamaishi M RE, Yarom N, Avni B, Leitersdorf E, Raz I, Elad S. Possible association between diabetes and bisphosphonate-related jaw osteonecrosis. J Clin Endocrinol Metab 2007;92:1172-75.
16. Reid IR, Cundy T. Osteonecrosis of the jaw. Skeletal Radiol 2009;38:107.
17. Henry D, von Moos R, Vadhan-Raj. A double-blind, randomized study of denosumab versus zoledronic acid for the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. (Abstract). Europ J Cancer Suppl. 2009;7(3):15th Congress of the European CanCer Organization (ECCO ) and the 34th European Society for Medical Oncology (th ESMO) Multidisciplinary Congress: Abstract 20LBA. Presented September 1, 2009. Disponible en: http://ex2.excerptamedica.com/CIW-09ecco/index.cfm?fuseaction=CIS2&hoofdnav=Abstracts&content=abs.details&what=FREE%20TEXT&searchtext=denosumab&topicselected=*&selection=ABSTRACT&qryStartRowDetail=1. pag 11.
18. Stopeck A, Body J, Fujiwara Yea. Denosumab versus zoledronic acid for the treatment of breast cancer patients with bone metastases: results of a randomized phase 3 study. Europ J Cancer Suppl. 2009;7(3): (Abstract) 15th Congress of the European CanCer Organization (ECCO ) and the 34th European Society for Medical Oncology (th ESMO) Multidisciplinary Congress: Abstract 20LBA. Presented September 1, 2009. Disponible en: http/ex2.excerptamedica.com/CIW-09ecco/index.cfm fuseaction=CIS2&hoofdnav=Abstracts&content=abs.details&what=FREE%20TEXT&searchtext=denosumab&topicselected=*&selection=ABSTRACT&qryStartRowDetail=2. pag 7.